1 / 36

CLEARANCE CONCEPTS

Text: Applied Biopharm. & PK L. Shargel, S Wu-Pong & A. Yu; 5th Ed. Chapter 6 (p131-158) Chapter 11 (p303-348). CLEARANCE CONCEPTS. Math problems? Call 1-800-[(10x)(13i)^2]-[sin(xy)/2.362x]. Clearance -Objectives for Today-.

jaafar
Download Presentation

CLEARANCE CONCEPTS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Text: Applied Biopharm. & PK L. Shargel, S Wu-Pong & A. Yu; 5th Ed. Chapter 6 (p131-158) Chapter 11 (p303-348) CLEARANCE CONCEPTS Math problems? Call 1-800-[(10x)(13i)^2]-[sin(xy)/2.362x]

  2. Clearance-Objectives for Today- • Review of methods to calculate total body clearance . • Understand the relative contribution of specific eliminating pathways on total body clearance. • Integration of clearance methods for the calculation of specific organ clearances and elimination rates.

  3. Def’n: PK term to describe the irreversible removal of drug from the body (drug elimination) Most important PK parameter because it determines Dose & Dosing schedule. Variable parameter- affected by age, disease, genetics … Clearance

  4. Can be used to describe drug elimination from either total body(CLT) or from a single organ ( ie. CLH ; CLR ; CLbile ; ).

  5. Given in Drug Monographs Mechanism of clearance not identified Sum total of processes: CLT = CLM+ CLR+CLBILE +... Total Body Clearance (CLT)

  6. Rather than describing in terms of amount of drug removed per unit time, Clearance isdescribed as volume of plasma cleared of drug per unit time (volume/time) 100 mg/L 1000 mg Drug L/hr 10 Litres Simplest case- a beaker…

  7. But the body’s not a beaker- multiple systems involved….. BODY Vd ke KIDNEY URINE IV DRUG LIVER kbile km Bile Metabolites

  8. Calculation of Clearance

  9. Clearance calculated using: Elimination Rate Constants. CLT = K (V) CL r (renal) = ke (V) CL m (metab) = km (V) CL bile = kbile (V) Add all processes & cancel out Volume terms … K = km + ke + kbile + …. METHOD 1. Beaker- Single Tap Analogy Processes contributing

  10. Model Dependent • 2 compartment model has distribution & elimination occurring. K = hybrid value • Need accurate measurement of K and V • Assumes First Order Kinetics are followed.

  11. In many drug monographs – I can only find information on the half-life and distribution. Isn’t this as good as clearance?

  12. Relationship between CLT andt½ CLT = KV CLT = 0.693 *V/ t½ t½ = 0.693 *V / CLT t½ inversely related to CLT t½also dependent on volume of distribution. K and t½ are dependent on both CLT &V Model Dependent K = 0.693/ t½

  13. Example: BODY Ke = 0.147 Vd = 44 L KIDNEY URINE IV DRUG Kbile = 0.331 LIVER Bile Km = 0.251 Metabolites Calculate the CLr, CLT and t ½ for this drug.

  14. Answer: CLr = ke * V CLT = K * V T½ = 0.693/K

  15. METHOD 2 Clearance calculated usingdrug concentrations: CL = (dX/dt) / C • Clearance is defined as rate of drug loss (from total body or organ) relative to the concentration of drug in plasma. • Model independent dX/dt = Rate of drug elimination C = Plasma (or blood) concentration

  16. RearrangingCL = (dX/dt) / C dX/dt = CL * C • Clearance can be calculated by plotting elimination rate versus drug concentration. • Slope will be equal to clearance • Clearance is a constant.

  17. Example : Calculation CLr Plot of Urinary Excretion Rate (dAe/dt) versus Drug Conc (mid-point) can be used to calculate CLr dAe/dt = CLr•C Slope = CLr dAe/dt calculate slope Plasma Drug Concentration • minimum of 2 determinations are needed

  18. Rather than plotting, clearance can also be calculated by integrating the equation over time. - This can be any time period, including time zero (t0) to infinity (t∞ )

  19. Based on previous equation: dAe/dt = (Clr)C Integrated to time (t1): Ae 0-t1 = (Clr) AUC 0-t1 CLr = Ae 0-t / AUC 0-t Integrated to infinity: CLr = Ae  / AUC Example : Calculating CLr Can be any time period 0-t; t1-t2  should collect urine for 5 t½: *Usually just calculated could also plot intervals

  20. Example: Drug X- administered IV. Plasma and urine collected for 12 hours. A total of 7.5 mg of Drug X was collected in urine during the 12 hour PK study. Plasma concentrations determined and AUCs calculated: AUC 0-12 = 2500 g*hr/L AUC 0- = 3400 g*hr/L CLr = ?

  21. Answer: 7.5 mg of Drug X was collected in urine during the 12 hour PK study. Therefore Ae 0-12 = 7.5 mg  Have to use AUC 0-12

  22. Total body clearance can be obtained by integrating this equation from time zero (t0) to infinity (t ). All drug eliminated by t  After IV Dose: CLT = DOSEiv/ AUC  Systemic clearance reflects total amount of time that drug resides in the body. * Model independent dX/dt 0-∞ = DOSE

  23. What if the patient is given an oral dose of the drug!! How can I calculate clearance?

  24. Non-IV (Extravascular) Doses • ** Need to account for bioavailability • After Oral dose: CLT= Fpo * DOSEpo/ AUC  Systemic clearance based onamount of drug which gets into the systemic circulation and residence time of drug in body.

  25. METHOD 3 Clearance calculated using: Physiological parameters of individual organs. CL organ = Q (ER) Q = Blood or plasma flow to organ ER = Extraction Ratio. The efficiency of organ to clear drug from blood/plasma. NB. Can only be used for single organs not CLT

  26. ER= 0 – 1.Can be calculated from differences between amount of drug entering and leaving organ. The proportion of drug entering organ that is eliminated/converted upon each pass through the organ. • ER = (Cin - Cout )/Cin Liver Blood IN Blood OUT Bile

  27. Example: The hepatic extraction ratio (ER) for morphine is 0.65 and has a distribution volume of 4 L/kg. Assuming a hepatic flow rate (Q) of 90 L/hr, what would be the expected hepatic clearance for morphine in a 70 kg man after an IV dose. CL H = Q (ER) CL H = 90 L/hr *(0.65) = 58.5 L/hr Will cover in more detail with more examples in hepatic lectures

  28. You will often need to use a combination of these three methods to calculate clearance. • Look at the information provided and determine which approach you should use for calculations.

  29. Organ Clearance often reported in different ways. Individual processes/ Organ Clearance may be described and calculated from Total body clearance . Addition/Subtraction of Clearance Routes Fraction of Total Body Clearance Reporting Clearance

  30. To Ilustrate : Renal Clearance (CLr) Renal Clearance (CLr) is one Component of CLT • Fraction of drug eliminated renally (fe) describes relationship between Renal Clearance (CLr) and Total Clearance (CLT). Also describes the relationship between ke to total body K fe = CLr = ke CLT K fraction excreted in urine =Ae/ DOSEIV (Ae=Total amount of drug excreted in urine)

  31. Sample Problem. • New Immunosuppressant- Noreject is cleared by both renal (60%) and non-renal excretion and has a V of 150L. In healthy patients, AUC of 1530 g.hr/L is obtained after a 100 mg IV dose. a) What is the half-life of Noreject? b) What is the predicted renal and non-renal clearance of Noreject? c) What is the urinary elimination rate constant (ke) of Noreject ?

  32. Solution- A. What is the Half-life? CLT= Dose/ AUC

  33. Solution- B. What is CLr and CLnr?

  34. Solution C. What is ke ?

  35. Can determine clearance based on: Plasma concentrations (Cp or AUC) Elimination rate constants Extraction efficiency of organ Can calculate relative contribution of individual clearance routes from total body clearance. Where are we now?

  36. Sample Problems to work on at home Applied Biopharm & PK, 5th edition p 158 # 3, 4, 5, 6, 9 P 348-50 # 1, 2, 11

More Related